Aspirin as a General Prophylactic in Cancer and
Cardiovascular Disease
Aspirin is a non-steroidal anti-inflammatory drug
from the salicylate family. Salicylates have been used by mankind for a long
time. In the form of willow bark, salicylates were used as analgesics during
since the time of Hippocrates (460-370BC) and their antipyretic effects have
been recognised for more than 200 years.
In its modern form, acetylsalicylic acid or aspirin
has a molecular formula C9H8O4 and its
structural formula follows:
Aspirin (http://www.significancemagazine.org/details/webexclusive/986723/Aspirin--a-wonder-drug.html
Accessed 07/12/2011 )
According to Bayer (www.wonderdrug.com/pain/asp_history.htm)
“in 1897, a German chemist with Friedrich Bayer and company was searching for a
treatment for his father’s arthritis pain and produced the first stable form of
a product introduced as Aspirin”. However other sources (Rang and Dale 2007)
reveal aspirin had been discovered much prior its commercialisation as a
medicinal product by Bayer, who have made astronomical profits from it.
Aspirin is mainly available as dispersible and
enteric coated tablets however suppositories, transdermal ointments and soluble
powders are available. There are also many products which include a combination
of aspirin and other drugs.
Aspirin’s mechanism of action is via the
cyclooxygenase (COX) system where it inhibits the COX activity by irreversible
acetylation of the system.
The table below shows the COX system by which cyclic
prostanoids are biosynthesised via enzymatically catalysed oxidation of
arachidonic acid.
The production of prostaglandins from arachidonic
acid and their physiological effects. PG indicates, prostaglandin;
COX exists in two isoforms, COX-1 and COX-2, COX-1
being present in the endoplasmic reticulum of most cells and is responsible for
the synthesis of homeostatic prostaglandins which regulate cell functions such
as gastro mucosal protection, maintenance of renal blood flow and regulation of
platelet activation and aggregation. Cox-2 is not present in plasma normally
but is induced by inflammatory stimuli and growth factors to produce
prostaglandins that result in inflammatory response.
Aspirin’s anti-thrombotic effect is due to the
inhibition of PGH-synthase in both COX-1 and COX-2 with both affected isoforms
failing to convert arachidonic acid to PGH2 hence a decrease in the
production of prostaglandins and Thromboxane A2 (TXA2).
TXA2 is required for platelet aggregation and vasoconstriction thus
platelet failure to produce it in the presence of aspirin results in aspirin’s
therapeutic effect as an anti-thrombotic. Prostacyclin production by vascular
epithelia inhibits platelet aggregation and induces vasodilation hence aspirin
inhibition counters vascular epithelial antithrombosis. However, epithelia is
capable of regeneration whereas platelet lifespan is approximately 10 days
,with this regeneration, the aspirin effect on epithelial COX is removed
leaving only the platelets affected throughout their lifespan. The result is an
overall antithrombotic effect in the vascular system.
The importance of platelets and their aggregation is
well established with respect to their role in cardiovascular disease and the
antithrombotic effect of aspirin has been linked to the prophylaxis and
treatment of various cardiovascular diseases.
A research in the role of aspirin in acute
myocardial infarction (AMI) has shown astonishing results. According to Awtry
& Loscalzo (2000), the Second International Study of Infarct Survival
(ISIS-2), 17187 patients presenting within 24 hours of the onset of a suspected
AMI received intravenous streptokinase (1.5MU) or 162.5mg of aspirin daily for
30 day, both or neither. At the end of the trial, patients receiving aspirin
therapy alone had 23% reduction in vascular mortality and nearly 50% reduction
in the risk of non-fatal reinfarction and stroke.
According to a meta-analysis (Berger, Brown and
Berker 2008) “Aspirin therapy was associated with a 21% reduction in the risk
of cardiovascular events (non-fatal MI, non-fatal stroke and cardiovascular
death) 26% reduction in the risk of non-fatal MI, 25% reduction in the risk of
stroke and 13% reduction in the risk of all-cause mortality. Among those with
ischaemic heart disease, aspirin was most effective at reducing the risk of
non-fatal MI and all-cause mortality, among those with cerebrovascular disease,
aspirin was most effective at reducing the risk of stroke.”
A meta-analysis by Anti-Platelet Trialist in 1994
shows that among 20 000 patients with a prior history of MI, aspirin therapy
decreased the risk of vascular events over 2 year treatment from 17.1% to
13.5%.
These results show a significant level in secondary
thrombotic event prophylaxis resulting from simple daily intake of aspirin.
This is very important as people who have suffered an AMI or ischaemia are at a
high risk or the event reoccurring. Aspirin’s antithrombotic effects have also
proven useful in patients who have just undergone vascular surgical procedures
such as angioplasty or intra coronary stenting. The drug prevents intraluminal
thrombogenesis which may block the vessel causing further complications. This
and secondary prophylaxis effect of aspirin has a cumulative effect to surgical
patients, which will result in a decrease in mortality from post-operative
complications.
Daily intake of low dose aspirin (75mg) has been
shown to provide primary prophylaxis of cardiovascular events with The Medical
Research Council’s General Practice Research Framework (1998) showing that high
risk individuals had a 20% risk reduction in ischaemic and cardiovascular
events.
Research has also linked aspirin in lowering cancer
mortality.
Tumour metastasis is a hallmark in malignancy which
is the leading cause of cancer mortality. Metastasis occurs as follows i.
Tumour cells escape original site attaching to the extra-cellular matrix (ECM)
ii. Degrade the ECM iii. Migrate via the ECMs.
Jiang et al (2001) establish that cancer cells show
an increased COX-2 expression. Matrix metalloproteinase (MMPs) are enzymes
involved in ECM degradation. E-cadherin is an important molecule mediating
cell-cell adhesion. Jiang et al (2001) show that aspirin treatment modulates
MMP and increase E-cadherin production in cancerous cells via COX-2 this supports
Reich et al (1996) who reported that COX inhibition converts human fibrasoma
cells to a non-invasive state. With other chemotherapy aspirin can therefore be
used to help confine cancerous cells, allowing easier drug targeting in
chemotherapy.
By taking the recommended dose for particular
individual circumstances, aspirin can be lifesaving with astonishing properties
ranging from traditional uses as an antipyretic and anti-inflammatory to more
advanced uses in cardiovascular and oncology health. Much research may still be
required and modifications of the present drug to increase specificity will
reduce its side effects and make aspirin one of man’s greatest achievements.
References
1. Awtry,E.H., Loscalzo,J., 2000
Aspirin Circulation 1206-1218
2. Berger,J.S., Brown,D.L.,
Becker,R.C., 2008 Low-Dose Aspirin in Patients with Stable Cardiovascular
Disease: A Meta-analysis The American
Journal of Medicine, Vol 121 43-49
3. Jiang,M., Liao,c., Lee,P., 2001
Aspirin Inhibits Matrix Metalloproteinase-2 Activity, Increases E-cadherin
Production and Inhibits in Vitro Invasion of Tumor Cells Biochemical and Biophysical Research Communications Vol
282 671-677
4. The Medical Research Council’s
General Practice Research Framework 1998 Thrombosis Prevention Trial: Randomise
Trial of Low-Intensity Oral Anticoagulation Ischaemic Heart Disease in Men at
Increased Risk Lancet Vol 351 233-241
5.
Rang,H.P.,
Dale,M.M., (2007) General Principles In: Riteer,J.M., Flower,R.J., Pharmacology 6th edn Churchill
Livingstone: Elsevier 3-7
6.
Reich,R.,
Martin,G.R., (1996) Identification of Arachidonic Acid Pathways Required For
the Invasive and Metastatic Activity of Malignant Tumour Cells. Prostaglandins Vol 51 1-17
By Takudzwa .K.Muswizu QD
